1. Field of the Invention
The present invention relates to a diagnostic agent for glycometabolic function comprising a glucose derivative as an active ingredient. In particular, the present invention relates to a diagnostic agent which is useful for indicating the glycometabolic function in a tumor site in various tumor diseases.
2. Background Information
Of energy sources necessary for activity of humans, in particular, glucose is taken up from the blood into cells through the glucose transporter (hereinafter, referred to as GLUT), enters into the metabolic pathway after being converted to glucose-6-phosphate by the action of hexokinase and forms energy-rich phosphate compounds such as adenosine triphosphate (ATP), which are utilized as energy sources in living organisms. Particularly, glucose is the unique and important energy source in brain. It is accepted that the change of GLUT is minor and conversion to glucose-6-phosphate from glucose by hexokinase is the rate-determining step in the glycometabolism in brain tissue. Therefore, diagnosis of glucose metabolism in brain by positron emission tomography (PET) has been conducted using radioactive fluorodeoxyglucose which acts in a manner similar to that of glucose in passage through the blood-brain barrier and in metabolism towards 6-phosphate compounds by the action of hexokinase.
It has been known that, also in cells having abnormality such as tumor cells, necessary energies are provided by glucose and the blood glucose level has a great influence on the glycometabolism. Since, however, changes in both the membrane transport and phosphorylation are more complicated, qualitative diagnosis of the pathological state of tumor by radioactive fluorodeoxyglucose has been considered difficult in spite of the fact that there have been many articles showing positive correlation between growth rate of tumors which is an indicator of malignancy of tumor and hexokinase activity.
It has been well known that 2-F-18!fluorodeoxyglucose (hereinafter, referred to as FDG) acts in a manner similar to that of glucose in the glycometabolic pathway, and it enters into cells with the aid of GLUT and is phosphorylated by the action of hexokinase. It is expected, on the other hand, that 1,3,4,6-tetra-O-acetyl-2-F-18!fluorodeoxyglucose (hereinafter, referred to as AFDG), an acetylation product of FDG, is taken up into cells without the aid of GLUT, hydrolyzed by an esterase to form FDG, which is phosphorylated by hexokinase similarly to FDG taken up into cells with the aid of GLUT. The behavior of them can be schematically shown in FIG. 8. As the result of an extensive study about the metabolic behavior of AFDG and FDG in tumor cells, the present inventors have discovered that a change in hexokinase activity can be detected on the basis of the fact that AFDG is taken up into cells without the aid of GLUT, quickly hydrolyzed by an esterase to form FDG, which is phosphorylated by hexokinase irrespective of extracellular glucose concentration, and successfully completed the present invention.
Thus, the purpose of the present invention is to provide a diagnostic agent useful for diagnosis of glycometabolic function using the compound which is taken up into cells without the aid of GLUT, immediately acts as a substrate for hexokinase and is metabolized in a manner similar to that of glucose and is able to be an indicator for hexokinase activity in the metabolism, particularly to provide a diagnostic agent therefor which is useful for indicating the glycometabolic function in a tumor site in various tumor diseases.